Pathogenic, emerging zoonotic viruses are increasing in frequency and becoming a major public health concern. In the past 15 years, two highly pathogenic Coronaviruses, Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) and Middle East Respiratory Syndrome coronavirus (MERS-CoV), have emerged. MERS-CoV was first identified in 2012 in the Kingdom of Saudi Arabia and continues to cause human infections in the Middle East. To date, MERS-CoV has caused over 2,100 infections in 27 countries with a case fatality rate of ~36%. Very little is known about MERS-CoV pathogenesis in humans;? however, a variety of epidemiological studies have been conducted to determine what factors contribute to disease severity. The largest risk factor for increased disease severity and death is diabetes. More than 415 million people worldwide have diabetes and 85-95% of these cases are due to type 2 diabetes (T2D). Diabetes is also incredibly common in the Middle East where the prevalence is more than 20%. It is not clear how diabetes contributes to increased disease severity in people infected with MERS-CoV. To better understand MERS-CoV pathogenesis and how diabetes affects this, we developed a novel mouse model in which this question can be studied. The cellular receptor for MERS-CoV is the surface molecule DPP4. Wildtype mice are not susceptible to MERS-CoV replication due to receptor differences in mice and humans, thus a transgenic mouse was developed in which the human DPP4 gene was knocked in to C57Bl/6 mice replacing the mDPP4 gene (hDPP4/B6). Preliminary experiments showed that T2D can be induced in hDPP4/B6 mice using a high fat diet and that diabetic mice exhibit a more prolonged and severe course of disease following MERS-CoV infection. Diabetic male mice appear to be the most affected. In Aim 1 of the study we are going to better define the pathogenesis of MERS-CoV infection in diabetic mice of both sexes by evaluating lung pathology, virus dissemination, replication, and clearance, and cellular receptor distribution and activity. Aim 2 focuses on determining how alveolar macrophages and infiltrating macrophage/monocytes contribute to MERS-CoV pathogenesis and how T2D affects this response. These studies will provide more information about immune-mediated mechanisms of disease in MERS-CoV infection and how diabetes alters this pathogenesis for the identification and development of better therapeutics.